Cyclic guanosine monophosphate (cGMP) is a second messenger that has been implicated in cochlear function. In the cardiovascular system, cGMP can be generated by natriuretic peptide (NP) stimulation of guanylyl cyclase. The proposed experiments will investigate the role of two NP receptors in cochlear homeostasis and pathology: NPR-A, a particulate guanylyl cyclase, and NPR-C, a clearance receptor that removes NPs from the circulation, resulting in decreased activation of NPR-A. In the inner ear, components of the NP system have been localized to the stria vascularis and spiral ganglion, but there are few functional studies of NPs. NPs are primary regulators of fluid transport in other tissues; therefore, our overarching hypothesis is that aberrations in the NP system alter endolymph composition, resulting in hearing loss. Preliminary studies have shown that only NPR-A stimulates cGMP production in the mouse cochlea, and that mutation of NPR-C results in a high frequency hearing loss. The proposed study has two specific aims. First, the effect of NPR-A ablation (i.e., a deficient guanylyl cyclase system) on inner ear function will be assessed in transgenic mice lacking NPR-A. Second, the effects of increased NPR-A activation (i.e., an overactive guanylyl cyclase stem) will be determined using mice deficient in NPR-C. In these experiments, endolymph potassium ion concentrations, endocochlear potentials and auditory brainstem responses will be used to assess cochlear function. In addition to the physiological measurements, guanylyl cyclase responses to NPs will be measured in vitro to ensure that the NP system is either attenuated or stimulated by the mutations. This study will provide critical information regarding the influence of this essential fluid regulating system on auditory function, potentially facilitating the development of novel treatments for disorders such as Meniere's disease and age-related hearing loss.